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Bugs Making Drugs

1 March 2001 7:00 pm
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Mix and match. By swapping or changing the modules that contain the active sites of polyketide synthases, researchers could engineer the enzymes to make novel polyketides in E. coli.

Researchers have coaxed a common lab bacterium, Escherichia coli, to produce large amounts of polyketides, the raw material for a large class of drugs that have often been difficult to produce. The findings may make manufacturing the drugs and creating new variants easier and cheaper.

Polyketides--which include such therapeutic mainstays as the antibiotic erythromycin, the immunosuppressive drug FK506, and the cholesterol-lowering drug lovastatin--have combined sales exceeding $10 billion per year. Because they're difficult to synthesize, companies rely on production by their natural sources--unusual soil bacteria and fungi. Many of these microbes are slow-growing and finicky, which makes them difficult to grow in the huge vats needed for industrial production. They're also tricky to alter genetically, hampering efforts to tweak the polyketide-synthesizing enzymes so that they make new variants.

E. coli is much easier to work with. But to make it produce polyketides, chemical engineer Chaitan Khosla of Stanford University and his colleagues had to overcome several hurdles. They first introduced three genes from a soil bacterium called Saccharopolyspora erythraea, which together produce an enzyme called a polyketide synthase, which produces one particular polyketide. But polyketide synthases don't work without a co-factor called phosphopantetheine, so the researchers also introduced a gene from the soil bacterium Bacillus subtilis that encodes the enzyme that attaches phosphopantetheine to the polyketide synthase. Finally, the researchers genetically altered two metabolic pathways to provide E. coli with the chemical building blocks needed to make the polyketide.

Their efforts paid off. In the 2 March issue of Science, the team reports that their bacterial strain can pump out the polyketide at rates approaching those of industrial S. erythraea strains. And by replacing one component of the S. erythraea polyketide synthase with a portion of an enzyme that makes a different type of drug, the Stanford team generated a hybrid enzyme that makes a polyketide unlike any found in nature. "I think it's a real breakthrough," says bioorganic chemist Heinz Floss of the University of Washington, Seattle.

Khosla and his colleagues still have a way to go to get industrial polyketide production by E. coli. But if they succeed, the work could lead to a big payoff for Khosla and a company he cofounded, Kosan Biosciences of Hayward, California. "We're going to ask now if we can use E. coli on a very large scale," says microbiologist Richard Hutchinson, Kosan's vice president of new technology.

Related sites
Kosan Biosciences
Review about polyketide synthesis in Science
Page about polyketides

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